Reduction in Late Mortality after Autologous Blood or Marrow Transplantation (autoBMT) in Childhood - a Report from the Blood or Marrow Transplant Survivor Study-2 (BMTSS-2)

Background: AutoBMT is used with a curative intent for several types of childhood cancer. However, there is paucity of information regarding the long-term outcome after autoBMT performed in childhood, and whether mortality rates have changed over the past 4 decades. We address these gaps by examining all-cause, relapse-related [RRM] and non-relapse-related [NRM] mortality in patients undergoing autoBMT between 1980 and 2010 at City of Hope, University of Minnesota or University of Alabama at Birmingham. Methods: To be included in this analysis, patients had to have received a single autoBMT before age 22y, and survived ≥2y after transplantation. Vital status information was ascertained as of December 31, 2016, using medical records, the National Death Index (NDI), and Accurint databases. Information on the cause of death was obtained from the NDI Plus program and medical records. Using Kaplan-Meier techniques, we describe overall survival conditional on surviving 2y and 15y from autoBMT. We describe cumulative incidence of RRM and NRM using competing risk methods. We also describe trends in all-cause mortality over 3 time periods: <1990, 1990-1999 and 2000-2010. Standardized mortality ratio (SMR) was used to compare the mortality of this cohort to the age- sex-, and calendar-specific mortality of the US general population. Proportional subdistribution hazards model (Fine-Gray) for competing risks was used for identifying predictors of late mortality (demographics, primary disease, conditioning agents, and disease status at autoBMT). Results: In this cohort of 364 2+y survivors of autoBMT performed in childhood, the most common primary diagnoses were Hodgkin lymphoma (HL: 26%), neuroblastoma (23%), acute myeloid leukemia (AML: 13%), acute lymphoblastic leukemia (ALL: 12%), and non-Hodgkin lymphoma (NHL: 9%). The distribution of the cohort over the 3 time periods was: <1990 (20%); 1990-1999 (37%); 2000-2010 (43%). After a median follow-up of 14.2y, 104 deaths were observed in this 2+y survivor cohort. The leading causes of death included primary disease (49.5%), subsequent malignant neoplasms (21.0%) and infection (18.2%). The 10y cumulative incidence of RRM (13.6%) exceeded that of NRM (10.2%) (Fig 1). Overall, the cohort was at a 23-fold higher risk of late mortality (SMR 23.6, 95% CI 19.3-28.6), when compared with the general population. The SMR was significantly increased in all groups of primary diagnoses; ALL (SMR 27.0), AML (SMR 7.8), HL (SMR 15.1), NHL (SMR 13.5), and neuroblastoma (SMR 60.7). Conditional on surviving 2y, 5y, 10y and 15y, the overall survival was 81.9%, 91.4%, 95.6% and 99.4%, respectively. Mortality rates continued to remain higher than the general population among those who had survived at least 10y after autoBMT (SMR 12.4, 95% CI 4.9-25.1), but approached those of the general population among the 15+y survivors (SMR 3.0, 95%CI, 0.5-9.4). The all-cause 10y cumulative mortality rate declined over the 3 eras (<1990: 35.1%, 1990-1999: 24.4%; 2000-2010: 20.6%, p=0.02) (Fig 2). Adjusting for demographic and clinical variables, as well as preparative regimens, the hazard ratio (HR) of all-cause mortality declined in the more recent treatment eras (<1990 (referent group): HR=1.0; 1990-1999: HR=0.5, 95%CI, 0.3-0.9, p=0.02; 2000-2010: HR=0.4, 95%CI, 0.2-0.8, p=0.007). Conclusion: Taken together, these findings suggest that the mortality rates of autoBMT recipients are significantly higher than those of the general population. Relapse is the leading cause of death for the first 10y after autoBMT. Importantly, there has been a significant decline in all-cause mortality in children undergoing autoBMT over the past 4 decades.

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